抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

THE DESIGN AND ANALYSIS OF EXPERIMENTS. By Oscar Kempthorne. New York, John Wiley and Sons, Inc., 1952. 631 pp. $8.50. This book by a teacher of statistics (as well as a consultant for \"experimenters\") is a comprehensive study of the philosophical background for the statistical design of experiment. It is necessary to have some facility with algebraic notation and manipulation to be able to use the volume intelligently. The problems are presented from the theoretical point of view, without such practical examples as would be helpful for those not acquainted with mathematics. The mathematical justification for the techniques is given. As a somewhat advanced treatment of the design and analysis of experiments, this volume will be interesting and helpful for many who approach statistics theoretically as well as practically. With emphasis on the \"why,\" and with description given broadly, the author relates the subject matter to the general theory of statistics and to the general problem of experimental inference. MARGARET J. ROBERTSON

The Design and Analysis of Experiments

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

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Initial sequencing and comparative analysis of the mouse genome.

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

https://science.sciencemag.org/content/sci/early/2015/03/11/science.aaa1348.full.pdf

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Computer models can be combined with laboratory experiments for the efficient determination of (i) peptides that bind MHC molecules and (ii) T-cell epitopes. For maximum benefit, the use of computer models must be treated as experiments analogous to standard laboratory procedures. This requires the definition of standards and experimental protocols for model application. We describe the requirements for validation and assessment of computer models. The utility of combining accurate predictions with a limited number of laboratory experiments is illustrated by practical examples. These include the identification of T-cell epitopes from IDDM-, melanoma- and malaria-related antigens by combining computational and conventional laboratory assays. The success rate in determining antigenic peptides, each in the context of a specific HLA molecule, ranged from 27 to 71%, while the natural prevalence of MHC-binding peptides is 0.1–5%.

Computational binding assays of antigenic peptides

Background The flavivirus genus is unusually large, comprising more than 70 species, of which more than half are known human pathogens. It includes a set of clinically relevant infectious agents such as dengue, West Nile, yellow fever, and Japanese encephalitis viruses. Although these pathogens have been studied extensively, safe and efficient vaccines lack for the majority of the flaviviruses. Results We have assembled a database that combines antigenic data of flaviviruses, specialized analysis tools, and workflows for automated complex analyses focusing on applications in immunology and vaccinology. FLAVIdB contains 12,858 entries of flavivirus antigen sequences, 184 verified T-cell epitopes, 201 verified B-cell epitopes, and 4 representative molecular structures of the dengue virus envelope protein. FLAVIdB was assembled by collection, annotation, and integration of data from GenBank, GenPept, UniProt, IEDB, and PDB. The data were subject to extensive quality control (redundancy elimination, error detection, and vocabulary consolidation). Further annotation of selected functionally relevant features was performed by organizing information extracted from the literature. The database was incorporated into a web-accessible data mining system, combining specialized data analysis tools for integrated analysis of relevant data categories (protein sequences, macromolecular structures, and immune epitopes). The data mining system includes tools for variability and conservation analysis, T-cell epitope prediction, and characterization of neutralizing components of B-cell epitopes. FLAVIdB is accessible at cvc.dfci.harvard.edu/flavi/ Conclusion FLAVIdB represents a new generation of databases in which data and tools are integrated into a data mining infrastructures specifically designed to aid rational vaccine design by discovery of vaccine targets. Background More than 70 known viral species belong to the flavivirus genus. The flavivirus genus can be divided into three clusters, fourteen clades, and 70 species [1]. The clusters are based on host-vector association: mosquito-borne, tick-borne, and no-vector viruses. The members of flavivirus clades share >69% pairwise nucleotide sequence identity, while members of individual species share >84% identity [1]. More than half of these singlestranded RNA viruses are known human pathogens [2]. The most important human pathogens among flaviviruses are West Nile virus (WNV), dengue virus (DENV), Tickborne encephalitis virus (TBEV), Japanese encephalitis virus encephalitis virus (JEV), and yellow fever virus (YFV). Flaviviruses pose a significant global public health threat since they are responsible for hundreds of

FLAVIdB: A data mining system for knowledge discovery in flaviviruses with direct applications in immunology and vaccinology.

Background: A wealth of information on clinical trials has been provided by publicly accessible online registries. Information technology and data exchange standards enable rapid extraction, summarization, and visualization of information and derived knowledge from these data sets. Clinical trials data was extracted in the XML format from the National Library of Medicine ClinicalTrials.gov site. This data includes categories such as \'Summary of Purpose\', \'Trial Sponsor\', \'Phase of the Trial\', \'Recruiting Status\', and \'Location\'. We focused on 645 clinical trials related to cancer vaccines. Additional facts on cancer types, including incidence and survival rates, were retrieved from the National Cancer Institute Surveillance data. Results: This application enables rapid extraction of information about institutions, diseases, clinical approaches, clinical trials dates, predominant cancer types in the trials, clinical opportunities and pharmaceutical market coverage. Presentation of results is facilitated by visualization tools that summarize the landscape of ongoing and completed cancer vaccine trials. Our summaries show the number of clinical vaccine trials per cancer type, over time, by phase, by lead sponsors, as well as trial activity relative to cancer type and survival data. We also have identified cancers that are neglected in the cancer vaccine field: bladder, liver, pancreatic, stomach, esophageal, and all of the low-incidence cancers. Conclusion: We have developed a data mining approach that enables rapid extraction of complex data from the major clinical trial repository. Summarization and visualization of these data represents a cost-effective means of making informed decisions about future cancer vaccine clinical trials.

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Data mining of cancer vaccine trials: a bird's-eye view

Recent years have witnessed an explosive growth in available biological data pertaining to autoimmunity research. This includes a tremendous quantity of sequence data (biological structures, genetic and physical maps, pathways, etc.) generated by genome and proteome projects plus extensive clinical and epidemiological data. Autoimmunity research stands to greatly benefit from this data so long as appropriate strategies are available to enable full access to and utilization of this data. The quantity and complexity of this biological data necessitates use of advanced bioinformatics strategies for its efficient retrieval, analysis and interpretation. Major progress has been made in development of specialized tools for storage, analysis and modeling of immunological data, and this has led to development of a whole new field know as immunoinformatics. With advances in novel high-throughput immunology technologies immunoinformatics is transforming understanding of how the immune system functions. This paper reviews advances in the field of immunoinformatics pertinent to autoimmunity research including databases, tools in genomics and proteomics, tools for study of B- and T-cell epitopes, integrative approaches, and web servers.

Bioinformatics for study of autoimmunity

The main goal of pharmacogenomics is to study the effects of genetic variation on patient responses to therapies. Its applications range from the evaluation of safety and efficacy of treatment to the optimization of therapies and therapeutic regimens. Pharmacogenomics is becoming increasingly important in immunology, for the development of new generation vaccines, immunotherapies and transplantation. The human immune system is a complex and adaptive learning system which operates at multiple levels: molecules, cells, organs, organisms, and groups of organisms. Immunologic research, both basic and applied, needs to deal with this complexity. We increasingly use mathematical modeling and computational simulation in the study of the immune system and immune responses. Thus, quantitative models that appropriately capture the complexity in architecture and function of the immune system are an integral component of the personalized medicine efforts. In silico models of the immune system can provide answers to a variety of questions, including understanding the general behavior of the immune system, the course of disease, effects of treatment, analysis of cellular and molecular interactions, and simulation of laboratory experiments. We herein present the ImmunoGrid project that integrates molecular and system level models of the immune system and processes for in silico studies of the immune function. The ImmunoGrid simulator uses Grid technologies, enabling computational simulation of the immune system at the natural scale, perform a large number of simulated experiments, capture the diversity of the immune system between individuals, and provide a basis for therapeutic approaches tailored to the individual genetic make-up.

Vladimir Brusic

Papers

Computational binding assays of antigenic peptides

FLAVIdB: A data mining system for knowledge discovery in flaviviruses with direct applications in immunology and vaccinology.

Data mining of cancer vaccine trials: a bird's-eye view

Bioinformatics for study of autoimmunity

Computational Simulations of the Immune System for Personalized Medicine: State of the Art and Challenges